Modulating SOS response induction by antimicrobial agents

Abstract

Compositions and methods are provided for the use of SOS pathway targeted agents in antimicrobial formulations. The innate sensitivity of bacteria to antibiotics is increased by disrupting a mechanism that normally activates the bacterial SOS response or by inhibiting steps in the SOS response pathway itself. SOS response induction can result from exposure of bacteria to certain antibiotics, including β-lactam antibiotics and other agents that affect cell wall synthesis. By transiently delaying bacterial cell division, SOS response induction interferes with bacterial killing by ordinarily lethal concentrations of these drugs A pharmaceutical composition comprising an SOS targeted agent is administered to a patient suffering from a microbial infection, in combination with an antibiotic that induces an SOS response. The identification of the SOS pathway as a target for modulating antibiotic action provides a basis for further therapeutic development, through screening assays designed to detect molecules or genes that act on these pathways.

1. A method of screening for an antibiotic enhancing agent, the method comprising:
 a) contacting a cell containing an SOS pathway polypeptide comprising dpiA, dpiB, recA, lexA or sfiA, with a candidate agent; 
 b) determining the effect of said agent on SOS pathway polypeptide function; and 
 c) determining the effect of said agent on said antibiotic function by 
 i) assaying the lethality of said antibiotic on said cell in the presence of said agent and in the absence of said agent, and 
 ii) comparing the said effects, 
 wherein increased lethality in the presence of said agent than in the absence of said agent indicates that the agent enhances antibiotic function; and wherein an antibiotic enhancing agent is one that disrupts said SOS pathway polypeptide function and enhances said antibiotic lethality.